DIETARY RESTRICTION AND THE TRANSCRIPTION FACTOR CLOCK DELAY EYE AGING TO EXTEND LIFESPAN IN DROSOPHILA MELANOGASTER

Abstract Many vital processes in the eye are under circadian regulation, and circadian dysfunction has emerged as a potential driver of eye aging. Dietary restriction (DR) is one of the most robust lifespan-extending therapies and amplifies circadian rhythms with age. We have previously shown that lifespan extension upon DR requires the presence of circadian clocks for maximal benefits. Herein, we demonstrate that dietary restriction extends lifespan in Drosophila melanogaster by promoting circadian homeostatic processes that protect the visual system from age- and light-associated damage. Altering the positive limb core molecular clock transcription factor, CLOCK, or CLOCK-output genes, accelerates visual senescence, induces a systemic immune response, and shortens lifespan. Flies subjected to dietary restriction are protected from the lifespan-shortening effects of photoreceptor activation. Inversely, photoreceptor inactivation, achieved via mutating rhodopsin or housing flies in constant darkness, primarily extends the lifespan of flies reared on a high-nutrient diet. Our findings establish the eye as a diet-sensitive modulator of lifespan and indicates that vision is an antagonistically pleiotropic process that contributes to organismal aging.

fitness by ensuring that appropriate activities occur at biologically advantageous times.Disruption of proper circadian timing negatively impacts organismal fitness, making understanding the mechanism underlying circadian regulation over cellular physiology critical to appreciating a fundamental rule of life on earth.As we age, our bodies circadian rhythms change due to stress, chronic disruption of our clocks, neurodegeneration, and a host of other reasons, which can have a profound effect on our systems.Therefore, understanding the aging circadian clock is important to promote longevity and healthy aging.In this session, we will investigate some of the research going on that links the clock to aging.Topics will include the investigation of the role of the clock in timing immunometabolic regulation in the context of inflammation and Alzheimer's disease, the optimization of the timing of exercise in the effort to maintain homeostasis and decrease risk, the connection between aging and the reduction of the number of rhythmically expressed genes and the weakening of circadian control, and the effect of dietary restriction on the circadian clock.The take home message of this session will be the importance of factoring daily time into research, preventative measures, and treatment regimens, to maximize overall health as we age.

CIRCADIAN TIMING OF THE IMMUNOMETABOLIC RESPONSE AFFECTS ALZHEIMER'S DISEASE PATHOLOGY Jennifer Hurley, Rensselaer Polytechnic Institute, Troy, New York, United States
Though the predominant model of the biological mechanisms underlying ADRDs is based on the beta-amyloid (Aβ) hypothesis, evidence suggests that inflammation from resident immune cells is also a key component of the development of ADRD pathophysiology.A major biological regulator of inflammation is the circadian clock, the 24-hour molecular timekeeper that broadly regulates gene expression throughout mammalian tissues to synchronize biology to the Earth's day/night cycle.Concordantly, chronic disruption of the circadian clock (CD) increases the risk for and severity of ADRDs.Our research has revealed that the circadian clock times metabolism, with the clock timing mitochondrial division which in turn times the response of mammalian macrophages to ADRD pathological factors.We show that subunits of the enzyme NOX2, a driver in the creation of reactive oxygen species (ROS) that uses metabolites to impart inflammation, are driven to oscillate in a 24 hr rhythm by the circadian clock in macrophages and microglia.Notably, oscillations in these NOX2 subunits are dysregulated when an organism undergoes CD, leading to an increase in the levels of ROS released by macrophages and microglia and elevating overall levels of inflammation.Given the apparent interconnection between inflammation, circadian rhythms, and ADRDs, an understanding of the circadian timing of the immune system could be exploited to develop treatments that alleviate ADRD symptoms, contribute to a potential cure, and prevent a population-wide increase in neurodegeneration due to a societal surge in CD.

AGE-ASSOCIATED DECLINE IN TISSUE CIRCADIAN CLOCK FUNCTION Karyn Esser, University of Florida, Gainesville, Florida, United States
Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience.Emerging evidence has demonstrated age-associated changes in circadian functions.To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups.We find age-dependent and tissue-specific clock output changes but these changes exhibit tissue specific patterns.In general, aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control.These REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging.We determined there were tissue specific changes in the phase distribution of REGs with the hypothalamus and skeletal muscle tissues of the old mice showing a large reduction with REG peak expression at only one phase of the day.Analyzing all expressed genes within a tissue for differences at four distinct times of day identified unique clusters of differentially expressed genes (DEGs).These outcomes identify non-circadian but temporally distinct age associated changes in gene expression.This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

DIETARY RESTRICTION AND THE TRANSCRIPTION FACTOR CLOCK DELAY EYE AGING TO EXTEND LIFESPAN IN DROSOPHILA MELANOGASTER Pankaj Kapahi, Buck Institute for Research on Aging, Novato, California, United States
Many vital processes in the eye are under circadian regulation, and circadian dysfunction has emerged as a potential driver of eye aging.Dietary restriction (DR) is one of the most robust lifespan-extending therapies and amplifies circadian rhythms with age.We have previously shown that lifespan extension upon DR requires the presence of circadian clocks for maximal benefits.Herein, we demonstrate that dietary restriction extends lifespan in Drosophila melanogaster by promoting circadian homeostatic processes that protect the visual system from age-and light-associated damage.Altering the positive limb core molecular clock transcription factor, CLOCK, or CLOCK-output genes, accelerates visual senescence, induces a systemic immune response, and shortens lifespan.Flies subjected to dietary restriction are protected from the lifespan-shortening effects of photoreceptor activation.Inversely, photoreceptor inactivation, achieved via mutating rhodopsin or housing flies in constant darkness, primarily extends the lifespan of flies reared on a high-nutrient diet.Our findings establish the eye as a dietsensitive modulator of lifespan and indicates that vision is an antagonistically pleiotropic process that contributes to organismal aging.

RUN FOR ANTI-AGING: EXERCISE TIMING SPECIFIES METABOLIC RESPONSES Shogo Sato, Texas A&M University, College Station, Texas, United States
Exercise has been widely recognized as an effective nonpharmacological intervention to delay aging and reduce the onset of chronic metabolic diseases such as type 2 diabetes and cardiovascular diseases.The metabolic response to exercise is influenced by factors such as frequency, intensity, duration, and modality.However, the role of the timing of exercise in activating metabolic pathways has remained an outstanding question.The circadian clock allows the organism to adapt to the cyclic environmental changes imposed by the earth's rotation, thereby placing temporal boundaries on physiological functions, including metabolic responses to exercise.Our recent studies performed unbiased highthroughput metabolomics of 8 different metabolic tissues in response to a single-bout acute treadmill exercise at different times of the day in mice, revealing that daily timing of exercise is a critical variable for the metabolic impact on different metabolic tissues.This indicates that timing is key to unlocking the benefits of exercise on metabolic health and anti-aging.Therefore, optimizing exercise outcomes following when to exercise is essential to establishing personalized exercise interventions aiming at health improvement and reducing the risk of chronic diseases associated with aging.Our ongoing research is studying the time-of-day-dependent metabolic responses to exercise in aged mice compared to young mice.The ultimate goal is to identify the best time for exercise to promote longevity and healthy aging.

CONNECTING THE DOTS: SUPPORTING OLDER ADULTS LIVING WITH HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS
Chair: Elliott Weinstein Co-Chair: Daniel Jimenez Discussant: Hetta Gouse Although people living with HIV are living longer than ever before, significant HIV-related physical and mental health disparities remain among older adults living with HIV (OALWH) due to issues related to advanced aging.HIVassociated neurocognitive disorders (HAND) are becoming increasingly common and have the potential to negatively impact the cognitive, motor, and psychological well-being of OALWH.However, more research on both predictors of HAND and interventions to support cognitively impaired OALWH is needed.This symposium offers insights along the spectrum of intervention development.Two presentations will focus on best identifying predictors of HAND among groups most at-risk up while the other three discuss tailoring and evaluating interventions to alleviate HAND-related symptoms within diverse samples of OALWH from across the country.The first presentation centers on how cerebrospinal fluid markers of Alzheimer's-related pathology can disentangle diagnosing HAND and amnestic mild cognitive impairment among OALWH in Southern California while the second highlights the role of grip strength in predicting frailty and cognitive impairment among OALWH living in South Florida.The third presentation assesses the feasibility, acceptability, and preliminary intervention effects of a physical activity intervention on cognition adapted for Latino OALWH in South Florida while the fourth examines qualitative feedback from several focus groups on adapting cognitive remediation group therapy as a hybrid group intervention for OALWH with cognitive concerns living in two Canadian provinces.Finally, the last presentation reviews findings of a 2-year randomized clinical trial examining speed of processing training on everyday functioning among OALWH in the U.S. Deep South.

HEALTH PROMOTION TO PREVENT AND REDUCE COGNITIVE DECLINE IN LATINOS LIVING WITH HIV/AIDS
Elliott Weinstein 1 , Marcela Kitaigorodsky 2 , Victoria Behar-Zusman 1 , and Daniel Jimenez 3 , 1. University of Miami,Miami,Florida,United States,Hollywood,Florida,United States,3. University of Miami Miller School of Medicine,Miami,Florida,United States Older Latinos living with HIV (LWH) are at increased risk for earlier onset of aging-related cognitive decline.HIVrelated cognitive impairments are observed in several domains including memory, reasoning/executive functioning, and speed of processing.Depression, a known neurocognitive risk, has been reported at five times the level among older Latinos LWH than in the general population, and older Latinos LWH are more likely to be sedentary, and not as actively engaged in pursuing changes in physical activity compared to their non-Latino White counterparts.Thus, this is a population that is particularly vulnerable to cognitive decline due to multiple risk factors.The aim of this study is to assess feasibility, acceptability, and preliminary intervention effects on cognition of the Happy Older Latinos are Active (HOLA) health promotion intervention.Thirty Latinos living with HIV with a mean age of 61.6 years (SD=6.1)were enrolled in a pilot single-arm trial.Participants were assessed at two time points on measures of cognitive and psychosocial functioning as well as biomarkers of cognition.In 7 months, we met our enrollment target with <5% of eligible participants refusing participation.Participants attended over 70% of sessions and 3 participants were lost to follow up.These results indicate that HOLA is an innovative health promotion program that is uniquely tailored to address the multiple concerns that are prevalent in this community in a nonstigmatizing and culturally acceptable manner.